Drug abuse remains one of the major problems confronting society. Levels and metabolism of the biogenic amines are altered by many of the drugs currently abused. The objective of this proposal is to study the effects of drugs which are abused on the enzymes regulating the synthesis of the biogenic amines. Initally attention will be focused on the amphetamines but other drugs including marihuana will also be investigated as work on the project progresses. Since interesting effects of amphetamines on tyrosine hydroxylase activity have already been observed in our laboratory, this enzyme will be studied in an effort to determine the mechanism by which amphetamines bring about this effect and the possible relationship of this enzyme to tolerance and tachyphylaxis. Since it is presumed that 5- hydroxytryptamine is also altered by abused drugs, the enzyme tryptophan hydroxylase will also be studied after large doses of drugs. After the effects of one drug alone on the biosynthetic enzymes have been ascertained, combinations of the abused drugs will be administered and the effects on the enzymes assessed. Not only will these studies have significant application in the area of drug abuse and drug interaction, but it is anticipated that relevant information will be obtained in the area of mental and neurological disease, including schizophrenia and parkinsonism.